MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL IRB#: 12-264 A(11) Amended: 06-APR-2016 Page 1 of 29 A Pilot Trial of Enoxaparin versus Aspirin in Patients with Cancer and Stroke MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL Principal Investigator/Department: Lisa DeAngelis, MD Neurology Co-Principal Investigator(s)/Department : Babak Navi, MD Neurology Investigator(s)/Department: Edward Avila, MD Elena Pentsova, MD Thomas Kaley, MD Alan Carver, MD Christian Grommes, MD Xi Chen, MD Craig Nolan, MD Antonio Omuro, MD Igor Gavrilovic, MD Ingo Mellinghoff, MD Adrienne Boire, MD PhD Mariza Daras, MD Eli Diamond, MD Jacqueline Stone, MD Alison Gilgan, NP Marcel Smith, NP Malbora Perezic-Mustafa, RN Mary Elizabeth Davis, RN Katherine Panageas, DrPH Bianca Santomasso, MD PhD Richard Phillips, MD PhD Efstathia Tzatha, MD Neurology Neurology Neurology Neurology Neurology Neurology Neurology, Neurology Neurology, Neurology Neurology Neurology Neurology Neurology Nursing Nursing Nursing Nursing Epidemiology and Biostatistics: Biostatistics Neurology Neurology Neurology Consenting Professional(s)/Department: Lisa DeAngelis, MD Babak Navi, MD Edward Avila, MD Elena Pentsova, MD Thomas Kaley, MD Alan Carver, MD Milan Chheda, MD Christian Grommes, MD Xi Chen, MD Craig Nolan, MD Antonio Omuro, MD Igor Gavrilovic, MD Ingo Mellinghoff, MD Eli Diamond, MD Mariza Daras, MD Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology Neurology
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MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL …€¦ · Igor Gavrilovic, MD Ingo Mellinghoff, MD Eli Diamond, MD Mariza Daras, MD Neurology Neurology Neurology Neurology Neurology
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MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
Amended: 06-APR-2016 Page 1 of 29
A Pilot Trial of Enoxaparin versus Aspirin in Patients with Cancer and Stroke
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL
Principal
Investigator/Department:
Lisa DeAngelis, MD Neurology
Co-Principal Investigator(s)/Department:
Babak Navi, MD Neurology
Investigator(s)/Department: Edward Avila, MD
Elena Pentsova, MD
Thomas Kaley, MD
Alan Carver, MD
Christian Grommes, MD
Xi Chen, MD
Craig Nolan, MD
Antonio Omuro, MD
Igor Gavrilovic, MD
Ingo Mellinghoff, MD
Adrienne Boire, MD PhD
Mariza Daras, MD
Eli Diamond, MD
Jacqueline Stone, MD
Alison Gilgan, NP
Marcel Smith, NP
Malbora Perezic-Mustafa, RN
Mary Elizabeth Davis, RN
Katherine Panageas, DrPH
Bianca Santomasso, MD PhD
Richard Phillips, MD PhD
Efstathia Tzatha, MD
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology,
Neurology
Neurology,
Neurology
Neurology
Neurology
Neurology
Neurology
Nursing
Nursing
Nursing
Nursing
Epidemiology and Biostatistics:
Biostatistics
Neurology
Neurology
Neurology
Consenting
Professional(s)/Department:
Lisa DeAngelis, MD
Babak Navi, MD
Edward Avila, MD
Elena Pentsova, MD
Thomas Kaley, MD
Alan Carver, MD
Milan Chheda, MD
Christian Grommes, MD
Xi Chen, MD
Craig Nolan, MD
Antonio Omuro, MD
Igor Gavrilovic, MD
Ingo Mellinghoff, MD
Eli Diamond, MD
Mariza Daras, MD
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
Neurology
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
Amended: 06-APR-2016 Page 2 of 29
Adrienne Boire, MD PhD
Bianca Santomasso, MD PhD
Jacqueline Stone, MD
Richard Phillips, MD PhD
Efstathia Tzatha, MD
Neurology
Neurology
Neurology
Neurology
Neurology
Participating Institution(s) PI’s Name Site ’s Role
New York-Presbyterian Hospital/Columbia University Medical Center
Randolph Marshall, MD
Data Collection
Weill Cornell Medical Center
Babak Navi, MD
Data Collection
OneMSK Sites
Manhattan
West Harrison
Basking Ridge
Commack
Please Note: A Consenting Professional must have completed the mandatory Human
Subjects Education and Certification Program.
Memorial Sloan-Kettering Cancer Center 1275 York Avenue
New York, New York 10065
Amended: 06-APR-2016 Page 3 of 29
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
multiple dose vials (300 mg/3.0 ml). It is administered subcutaneously once or twice a day
depending on the indication. Commercially available drug will be used for this study.
Aspirin (originally Bayer ®), also known as acetylsalicylic acid, is an over-the-counter
salicylate drug manufactured by numerous pharmaceutical companies, that has an
antiplatelet effect by inhibiting the production of thromboxane. It is approved by the FDA for
the prevention and treatment of stroke, coronary artery disease, and myocardial infarction, as
well as the treatment of rheumatological conditions and pain. It is administered orally or per
rectum, and is available in chewable, enteric-coated, immediate-release, and controlled-
relase forms; available doses include 60, 81, 120, 162, 200, 300, 325, 500, 650, 800, and
975 mg. For this study, subjects will be told to preferentially purchase regular immediate-
release 81 mg tabs for oral use . However, other oral formulations (e.g., chewable, enteric-
coated, or controlled-release forms) and higher doses up to 325 mg per day will also be
allowed. Commercially available drug will be used for this study.
6.0 CRITERIA FOR SUBJECT ELIGIBILITY
Any adult patient with active systemic cancer diagnosed with acute ischemic stroke at the
main MSKCC campus, any of MSKCC’s outpatient centers, WCMC or at NYPH/CUMC,within
the prior four weeks would be eligible.
6.1 Subject Inclusion Criteria
• 18 to 85 years of age.
• Active cancer, defined as a pathologic diagnosis of or treatment for any cancer, other than basal-cell or squamous-cell carcinoma of the skin, within the past six months; or patients with known recurrent or metastatic disease within the past six months. A pathology report issued at the enrolling site confirming the diagnosis of cancer is required for study enrollment.
• Acute ischemic stroke within the prior four weeks, defined as a new neurologic
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IRB#: 12-264 A(11)
Amended: 06-APR-2016 Page 7 of 29
or radiologic indication of a non-cerebrovascular mimic, such as a brain metastasis, as the etiology of the deficit(s).
6.2 Subject Exclusion Criteria
• Inability to get brain MRI
• Known malignant primary brain tumor.
• Diagnosis of intracranial hemorrhage within the past 3 months, including intratumoral hemorrhage into brain metastases from a systemic cancer
• Active or serious bleeding within two weeks of enrollment.
• Patient condition associated with a high risk of bleeding such as recent surgery or peptic ulcer disease.
• Clear indication for anticoagulation (e.g., atrial fibrillation) anticipated during the study period.
• Clear indication for antiplatelet agents (e.g., cardiac stents); a patient receiving aspirin for primary prevention prior to index stroke may be enrolled as long as study investigators believe it would be safe for the patient to stop aspirin if the patient was randomized to the enoxaparin arm.
• Active bleeding diathesis.
• Platelet count of ≤ 70,000/mm3, an international normalized ratio (INR) > 1.6, or a partial thromboplastin time (PTT) > 40 seconds.
• Known allergy to heparin or aspirin or a history of heparin induced thrombocytopenia.
• Serum creatinine > 2 mg/dl.
• AST or ALT > 200 U/L. • Hemoglobin < 8 gm/dl
• Symptomatic carotid stenosis.
• Active pregnancy. • Life expectancy < 1 month or current hospice care
• Unavailability for follow-up.
7.0 RECRUITMENT PLAN
A total of 40 patients will be recruited from the Neurology inpatient and consultation
censuses at the main MSKCC campus, MSKCC outpatient centers, WCMC and
NYPH/CUMC through screening conducted by research and clinical staff during normal
business hours. MSKCC is expected to accrue 6 patients per year, while CUMC and WCMC
are each expected to accrue 4 patients per year. All patients enrolled into the trial must sign
written informed consent. There are no gender or racial restrictions.
In order to satisfy all of the study’s feasibility endpoints, MSKCC, WCMC and NYPH/CUMC
staff will screen all ischemic stroke patients and will systematically record the total number of
patients with ischemic stroke, the total number with ischemic stroke and active systemic
cancer, the total number that are eligible for the trial (and if not eligible the reason(s) why),
the total number approached for enrollment, and the total number enrolled.
Patients who drop out of the study before the 3-month timepoint for reasons other than a
safety or efficacy event or death will be replaced.
Potential research subjects will be identified by a member of the patient’s treatment team, a
protocol investigator, or research team. If the investigator is a member of the treatment team,
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he or she will screen their patient’s medical records for suitable research study participants
and discuss the study and their potential for enrolling in the research study. Potential
subjects contacted by their treating physician will be referred to the investigator/research
staff of the study.
The principal investigators may also screen the medical records of patients with whom they
do not have a treatment relationship for the limited purpose of identifying patients who would
be eligible to enroll in the study and to record appropriate contact information in order to
approach these patients regarding the possibility of enrolling in the study.
During the initial conversation between the investigator/research staff and the patient, the
patient may be asked to provide certain health information that is necessary to the
recruitment and enrollment process. The investigator/research staff may also review portions
of their medical records in order to further assess eligibility. They will use the information
provided by the patient and/or medical record to confirm that the patient is eligible and to
contact the patient regarding study enrollment. If the patient turns to to be ineligible for the
research study, the research staff will destroy all information collected on the patient during
the initial conversation and medial records review, except for any information that must be
maintained for screening log purposes.
In most cases, the initial contact with the prospective subject will be conducted either by the
treatment team, investigator, or the research staff working in consultation with the treatment
team. The recruitment process outlined presents no more than minimal risk to the privacy of
the patients who are screened and minimal PHI will be maintained as part of a screening log.
For these reasons, we seek a (partial) limited waiver of authorization for the purposes of (1)
reviewing medical records to identify potential research subjects and obtain information
relevant to the enrollment process; (2) conversing with patients regarding possible
enrollment; (3) handling of PHI contained within those records and provided by the potential
subjects; and (4) maintaining information in a screening log of patients approached (if
applicable).
This limited waiver will apply only to MSKCC. Any participating sites that require a limited
waiver must obtain it from their own local IRB/Privacy Board (PB) via a separate protocol
addendum or request. It is the responsibility of the MSKCC staff to confirm the participating
data collection site(s) have a limited waiver approved by their local IRB(s)/PBs.
8.0 PRETREATMENT EVALUATION
The following studies are required within four weeks of registration, all of which are routinely
performed as part of standard practice in patients with active cancer and acute stroke:
• Complete history and physical exam including neurological exam.
• Modified Rankin Scale.
• NIH Stroke Scale.
• Karnofsky Performance Status Scale.
• Height and weight.
• CBC including WBC differential and platelet count.
• Coagulation studies, including PT, PTT, and INR.
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• Serum D-Dimer and fibrinogen level.
• Comprehensive chemistry panel (see appendix F).
• Electrocardiogram (EKG).
• Carotid artery imaging with MRA, CTA, or ultrasound.
• MRI scan of the brain (contrast is not required).
The complete history and physical examination, height and weight, CBC, coagulation
studies, comprehensive chemistry panel (see appendix F), EKG, carotid artery imaging, and
MRI of the brain must be performed before registration, while the other required studies may
be performed after registration as long as they are done within two weeks after the date of
registration.
9.0 TREATMENT/INTERVENTION PLAN
9.1 Subcutaneous Enoxaparin
Half the study patients (n=20) will be randomized to subcutaneous enoxaparin. This medicine
will be injected twice daily at a dose of 1 mg/kg with a maximum starting dose of 100 mg BID.
Patients who weigh more than 100 kg will start at a dose of 100 mg BID; their subsequent
dosing will be guided by hematology and may change. Treatment is routine, and should
begin within 7 days of randomization (either inpatient or outpatient) and continue for 6
months. A registered nurse will teach patients randomized to the enoxaparin arm how to
perform subcutaneous injections; in cases of significant patient handicap, a surrogate of the
patient will be taught to perform the injections.
9.2 Oral Aspirin
The other half of study patients (n=20) will be randomized to oral aspirin. The medicine will
be administered daily at a dose of 81 mg unless a concomitant medical condition, such as
coronary artery disease, dictates a higher dose of aspirin to be administered instead
(maximum dose 325 mg daily). Treatment is routine, and should begin within 7 days of
randomization (either inpatient or outpatient) and continue for 6 months.
9.3 Medications to Avoid
The following medications should be avoided during the course of the study in order to
reduce the risk of bleeding side effects: clopidogrel (Plavix®), prasugrel (Effient®), ticlopidine
• <1%: allergic reaction, renal dysfunction, hearing loss or tinnitus.
If a patient is discovered at any time to have a platelet count < 70,000/mm3, hemoglobin < 7
gm/dl, PTT > 80 seconds, INR > 3, or creatinine > 2.5 mg/dl because of chemotherapy or
other medical reasons, then the patient’s study drug will be temporarily discontinued and
weekly, relevant blood tests will be performed. The study drug will only be reinstituted if the
abnormal laboratory values return to acceptable levels as deemed by the principal and/or co-
principal investigator. Treating physicians will also be encouraged to contact study
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Amended: 06-APR-2016 Page 13 of 29
investigators whenever there is concern for a heightened bleeding risk, so that more vigilant
monitoring is performed.
To ensure that the study medications are not excessively increasing the rates of serious
adverse events, an external data and safety monitoring board as detailed in Section 16.2 will
periodically review all potential adverse events and will have the authority to stop further
enrollment into the study if unacceptable rates of hemorrhage or death are discovered.
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT
Primary safety and secondary efficacy outcomes will be assessed for by a study investigator
at 1 month (+/- 1 week), 3 months (+/- 1 week), and 6 months (+/- 1 week) after initiation of
treatment by interviewing the patient and/or surrogate via an in-person visit or phone
conversation and by reviewing any relevant medical records. The occurrence of an outcome
will be dichotomized as yes or no, although a single patient may have multiple outcomes.
The outcomes of interest are defined as follows:
Safety Outcomes
Intracranial Hemorrhage: Acute extravasation of blood into the brain parenchyma,
subarachnoid space, subdural space, or epidural space as demonstrated by neuroimaging,
surgical exploration, or autopsy.
Symptomatic Intracranial Hemorrhage: Intracranial bleeding associated with any clinical
deterioration or associated with death.
Major Bleeding: Bleeding associated with death; any intracranial hemorrhage; or a systemic
hemorrhage requiring hospitalization, blood transfusion, or surgery.
Efficacy Outcomes
Ischemic Stroke: New neurologic deficit(s) with CT or MRI evidence of acute ischemia in a
referable location, and no clinical or radiologic indication of a non-cerebrovascular mimic as
the etiology of the deficit(s).
Transient Ischemic Attack: Transient neurologic deficit lasting less than 24 hours, attributed
to focal brain ischemia without evidence for another etiology or cerebral infarction on CT or
MRI.
Myocardial Infarction: Any combination of two of the following three criteria: chest pain,
elevated cardiac enzymes (as per specific laboratory guidelines), or dynamic ECG changes
consistent with ischemia.
Deep Vein Thrombosis: Thrombosis of the deep venous circulation diagnosed via Doppler
examination, magnetic resonance venography, or spiral CT.
Pulmonary Embolus: Thrombosis of the pulmonary circulation diagnosed by spiral CT of the
chest or V/Q scan.
Systemic Arterial Thrombosis: An acute vascular occlusion of an extremity or organ,
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Amended: 06-APR-2016 Page 14 of 29
documented by means of imaging, surgery, or autopsy.
Though our primary objective is to assess the safety and feasibility of the interventions, we
will also assess functional outcomes at approximately 1 month, 3 months, and 6 months after
initiation of treament using the mRS score, NIHSS, and KPSS.
13.0 CRITERIA FOR REMOVAL FROM STUDY
If at anytime the patient develops unacceptable toxicity such as major bleeding, intracranial
hemorrhage, or a severe allergic reaction, he or she will be removed from the study.
If at anytime the patient is found to be ineligible for the protocol as designated in the section
on Criteria for Subject Eligibility (i.e., a change in diagnosis), the patient will be removed from
the study.
If at anytime the patient withdraws consent for continued participation or dies, he or she will
be removed from the study.
14.0 BIOSTATISTICS
Patients will be randomized at registration to receive 6 months of subcutaneous enoxaparin
or 6 months of oral aspirin. Please see section 15.2 for details about this process.
The enrollment rate will be the proportion of eligible patients who enroll in the study. The
study will be considered feasible if the lower bound of the 95% confidence interval (CI) of the
enrollment rate exceeds 30%. Therefore, our feasibility criterion will be met if 40 of the first
100 (40%; 95% CI, 30.3-50.3%) screened and eligible patients enroll. However, even if our
feasibility criterion is not met, we will continue to target up to another 50 patients (for a total
of 150 targeted patients) in an attempt to enroll 40 patients and thus obtain sufficient
preliminary data on safety outcomes. Assuming at least a 30% recruitment rate in eligible
patients and a 10% dropout rate among randomized patients, and given that MSKCC,
WCMC and CUMC care for approximately 280 total patients with cancer and recent stroke
per year, and roughly 15% of these patients would be eligible for this trial (based on 2015
data and the current eligibility criteria), we anticipate a total enrollment period of 5 years for
our pre-planned sample size of 40 patients. Therefore, since the trial started January 2013,
we anticipate that it will be completed by July 2018.
Because this is a pilot trial, the main aim of the study will be to assess the feasibility of
enrollment and randomization and the safety of the intervention regimens. However, several
secondary efficacy outcomes will also be assessed to enable accurate sample size
calculations for a future, larger, multi-center trial that will be sufficiently powered to detect
clinically relevant differences in efficacy outcomes. All outcomes will be assessed for
occurrence approximately at 1 month, 3 months, and 6 months after initiation of the study
drug, and are defined in detail in the Criteria for Therapeutic Response/Outcome
Assessment section.
The primary feasibility outcome will be the enrollment rate among eligible patients (i.e.,
screened patients that fulfill all subject inclusion and exclusion criterion regardless of whether
they are approached for enrollment by a study investigator); our target enrollment rate is
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≥30%. Patients who enroll into the study but then dropout or crossover will still be considered
successfully enrolled.
Secondary feasibility outcomes will be the dropout or crossover rate among randomized
patients and the study drug adherence rate among enrolled patients; the target dropout or
crossover rate is ≤20% and the target adherence rate is ≥75%. Study drug adherence is
considered a dichotomous variable for individual patients in this study and will be determined
by the 8-point MMAS. Patients whose mean total MMAS score is ≥6 will be considered
adherent. As noted in section 7.0, patients who drop out of the study before the 3-month
timepoint for reasons other than a safety or efficacy event or death will be replaced.
The primary safety outcomes will consist of intracranial hemorrhage, symptomatic intracranial
hemorrhage, major bleeding, and death. Because the study’s target sample size is small and
our secondary aim is to only obtain preliminary data on the safety of study drugs (not to
perform formal analysis of safety data), there will be no pre-specified stopping rule for this
study. However, an external MSKCC data and safety monitoring board will periodically review
all potential adverse events and will have the authority to stop further enrollment based on
any safety concerns.
Secondary efficacy outcomes will include: recurrent ischemic stroke; all strokes (ischemic or
hemorrhagic); a thromboembolic event composite consisting of recurrent ischemic stroke,
transient ischemic attack, myocardial infarction, deep vein thrombosis, pulmonary embolism,
or systemic arterial thrombosis; the modified Rankin Scale at 1, 3 and 6 months (van Swieten
et al 1988); the National Institute of Health Stroke Scale at 1, 3 and 6 months (Brott et al
1989); and the Karnofsky Performance Status Scale at 1, 3 and 6 months.
Descriptive statistics will be used to characterize the rates of eligibility, recruitment,
randomization, dropout, and adherence. The chi-square test will be used to compare the
rates of safety and efficacy outcomes between groups for dichotomous variables, and
analysis of covariance (ANCOVA) will be used to evaluate differences in continuous
variables over time accounting for pre-treatment values. Our primary analysis will use the
intention-to-treat principle, but we will also perform a secondary as-treated analysis.
Therefore, for our primary (intention-to-treat) analysis, outcomes will be analyzed according
to patients’ randomized study drug, regardless of prior anti-thrombotic use in the period
between stroke onset and study drug initiation or the duration of study drug.
Since this is a pilot trial primarily intended to assess safety and feasibility, we will be
underpowered to detect any significant differences between groups for our secondary
efficacy outcomes. However, this pilot trial will enable us to better estimate event rates in our
population, and thus more accurately perform sample size calculations in the future for a
fully-powered trial.
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES
15.1 Research Participant Registration
Confirm eligibility as defined in the section 6.0, entitled Criteria for Patient/Subject Eligibility.
Obtain informed consent, by following procedures defined in section 18.0, entitled Informed
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Consent Procedures.
During the registration process, registering individuals will be required to complete a protocol
specific Eligibility Checklist.
All participants must be registered through the Protocol Participant Registration (PPR) Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration System (http://ppr/). The completed signature page of the written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant documents must be uploaded via the PPR Electronic Registration System.
15.1.1 For Participating Sites
Central registration for this study will take place at MSKCC.
To complete registration and enroll a participant from another institution, the study staff at
that site must contact the designated research staff at MSKCC to notify him/her of the
participant registration. The site staff then needs to fax or email the registration/eligibility
The following documents must be sent for each enrollment within 24 hours of the informed
consent form being signed:
• The completed or partially completed MSKCC eligibility checklist
• The signed informed consent and HIPAA Authorization form
• Supporting source documentation for eligibility questions (laboratory results, pathology report, radiology reports, MD notes, physical exam sheets, medical history, prior treatment records, and EKG report).
Upon receipt, the research staff at MSKCC will conduct an interim review of all documents.
If the eligibility checklist is not complete, the patient will be registered PENDING and the site
is responsible for sending a completed form within 30 days of the consent.
If the eligibility checklist is complete, the participant meets all criteria, all source documentation is received, the participating site IRB has granted approval for the protocol, and the site is in good standing with MSKCC, the MSKCC research staff will send the completed registration documents to the MSKCC PPR Office to be enrolled as stated in section 15.1. The participant will be registered.
Once eligibility has been established and the participant is registered, the participant will be
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant
number). This number is unique to the participant and must be written on all data and
correspondence for the participant. This protocol participant number will be relayed back to
study staff at the registering site via e-mail and will serve as the enrollment confirmation.
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15.2 Randomization
After eligibility is established and consent is obtained, patients will be registered by MSKCC in
the PPR system and randomized using the CRDB. The treatment group to which the
participant was assigned to will be available right after registration, by calling the MSKCC
PPR registry between the hours of 8:30 AM and 5:30 PM, Monday through Friday, or by login
in the Clinical Research Database Web Client (CRDBi); randomization of eligible patients will
only occur during these times. Randomization codes will be generated in the CRDB.
Since patients with adenocarcinomas may be intrinsically more hypercoagulable than
patients with other tumor types (Seok et al 2010), stratified blocked randomization will be
undertaken to ensure similar numbers of patients with these carcinomas in each group.
Participating sites will receive a formal notification about the randomization status as soon as
this becomes available.
16.0 DATA MANAGEMENT ISSUES
A MSKCC Research Study Assistant (RSA) will be assigned to the study. The responsibilities
of the RSA include project compliance, data collection, data abstraction and entry, data
reporting, regulatory monitoring, problem resolution and prioritization, and coordination of
activities amongst the protocol study team.
All collected data will be entered into a secure, password-encrypted database at MSKCC
(CRDB), which only key study personnel will have access to. Source documentation will be
available to support the computerized patient record.
16.0.1. Data and Source Documentation for Participating Sites
Data The participating site(s) will enter data remotely into MSKCC’s internet-based Clinical Research Database, termed CRDBi-Multicenter. Standardized Case Report Forms (eCRFS) and data entry guidelines have been generated for this study. The site staff will receive CRDB training prior to enrolling its first patient. The participating site PI is responsible for ensuring these forms are completed accurately and in a timely manner. A schedule of required forms is shown in the table below. Participating sites will be responsible for completing eCRFs and submitting them to MSKCC per the designated timelines.
Source Documentation Source documentation refers to original records of observations, clinical findings and evaluations that are subsequently recorded as data. Source documentation should be consistent with data entered into eCRFs. Relevant source documentation to be submitted throughout the study includes:
• Baseline MRI that confirms evidence of acute ischemic stroke
• A pathology report issued in the enrolling site confirming this diagnosis is required for study enrollment.
• Treatment records • Required protocol assessment documents
• Grade 3-5 toxicities/adverse events
Source documentation should include a minimum of two identifiers to allow for data
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verification. MSK will maintain the confidentiality of any subject-identifiable information it may encounter.
16.0.2 Data and Source Documentation Submission for Participating Sites
Participating sites should enter data directly into CRDBi-Multicenter and study-specific eCRFs. Source documentation should be sent to MSKCC at the contact provided below. Submissions should include a cover page listing all source documentation enclosed per participant.
Department of Neurology Clinical Research Team Attn: Benjamin Weill, RSA 633 3rd Avenue, 12th Floor New York, NY 10017 [email protected] Phone: 646-227-2610 Fax: 646-227-2461
Participating sites are required to keep copies of each form that is sent via postal mail.
16.0.3 Data and Source Documentation Submission Timelines for Participating Sites
Data and source documentation to support data should be transmitted to MSKCC according to the following chart:
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Data and Source Submission Requirements and Timelines for Therapeutic Studies
Baseline
Treatment
start
Treatment
day 15
1
month
visit
3
month
visit
6 month
visit/Off
treatment
Serious
Adverse
Events
Survival
Follow
up/Off
study
Submission Schedule
Source
documentation
Within 24
hours (see
section
15.1.1)
w ithin 14 days of visit
Within 3
days of
event (see
section
17.2.1);
updates to
be submitted
as available
w ithin 14
days of
visit
eCRF
Within 7
days of
registration
Required Forms
Minimal Dataset:
Patient Information X
Minimal Dataset:
Initial Disease Info X
Minimal Dataset:
Disease Status X X
Minimal Dataset:
Histology X
Minimal Dataset:
Outcome Info X X X
Minimal Dataset:
Patient Status X X X X X X X
General Forms:
Comorbidity X X X X X
General Forms:
Concomitant Drug X X X X X
General Forms:
Diagnostic Test X
General Forms:
Laboratory
X X
X
General Forms:
Pathology X
General Forms:
Physical Exam X X X X X
General Forms:
Prior Therapy X
General Forms:
Toxicity X X X X x X X
General Forms:
Treatment X X X X X
General Forms:
Hospitalization X X X
General Forms:
Serious Adverse
Event
X
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
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Off-Study Requirements
When a patient is taken off-study, any outstanding data and required source documentation are required to be sent to MSKCC no later than 14 calendar days after the off-study date. Failure to submit required forms in the timelines requested may result in suspension of accrual privileges at a given site until data is updated, and/or withholding of contract payments if applicable.
The MSKCC PI may request from outside sites imaging documenting any PR or CR.
16.0.4 Data Review and Queries for Participating Site Data
Research staff at MSKCC will review data and source documentation as it is submitted. Data will be monitored against source documentation and discrepancies will be sent as queries to the participating sites. Queries will be sent by MSKCC Research staff twice a month.
Participating sites should respond to data queries within 14 days of receipt.
16.1 Quality Assurance
Weekly registration reports will be generated to monitor patient accruals and completeness
of registration data. Routine data quality reports will be created to assess for any missing or
inconsistent data. In addition, accrual rates and the extent and accuracy of outcome
assessments and follow-up will be monitored periodically throughout the study period, and
any potential issues will be immediately brought to the attention of the study team for
discussion and rectification, if necessary.
The study team will also perform random-sample data quality and protocol compliance audits
at least two times per year to ensure the integrity of the data.
16.1.1 Quality Assurance for Participating Sites
Each site participating in the accrual of participants to this protocol will be audited by the staff of the MSKCC study team for protocol and regulatory compliance, data verification and source documentation. Audits may be accomplished in one of two ways: (1) selected participant records can be audited on-site at participating sites or (2) source documents for selected participants will be sent to MSKCC for audit. Audits will usually be determined by participant accrual numbers and rate of accrual, but can also be prompted by reported SAEs or request of MSKCC PI.
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, annually during the study (or more frequently if indicated), and at the end or closeout of the trial. The number of participants audited will be determined by available time and the complexity of the protocol.
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The audit will include a review of source documentation to evaluate compliance for:
• Informed consent documents and procedures
• Adherence to eligibility criteria
• Protocol defined treatment • Required baseline, on study and follow-up protocol testing
• Case Report Form submissions to MSKCC: timeliness and accuracy
A wrap-up session will be conducted at the participating site and preliminary findings will be discussed with the participating site PI and research team. The preliminary results will be sent to the MSKCC PI.
Each audit will be summarized and a final report will be sent to the PI at the audited participating site within 30 days of the audit. The report will include a summary of findings, participant by participant case review, specific recommendations on any performance and/or shortcomings and request for corrective action, when necessary. When corrective action is required, the participating site must reply within 45 days of receipt of audit report with their corrective action plan.
A copy of the audit report and corrective action plan (if applicable) submitted by the participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the department’s protocol regulatory binder.
16.2 Data and Safety Monitoring
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center
were approved by the National Cancer Institute in September 2001. The plans address the
new policies set forth by the NCI in the document entitled “Policy of the National Cancer
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at
MSKCC were established and are monitored by the Office of Clinical Research. The
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
procedures will be established at the time of protocol activation.
16.3 Regulatory Documentation
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this protocol at the participating sites, approval for the MSKCC IRB/PB approved protocol must be obtained from the participating site’s IRB.
The following documents must be provided to MSKCC before the participating site can be initiated and begin enrolling participants:
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form
and HIPAA authorization
• Participating Site IRB approved consent form
• Participating Site IRB membership list • Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number
• Curriculum vitae and medical license for each investigator and consenting professional
• Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site
• Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at each participating site.
• Participating site laboratory certifications and reference ranges
Upon receipt of the required documents, MSKCC will formally contact the site and grant permission to proceed with enrollment.
16.3.1 Amendments
Each change to the protocol document must be organized and documented by MSKCC and
first approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC
will immediately distribute all non expedited amendments to the participating sites, for
submission to their local IRBs.
Participating sites must obtain approval for all non expedited amendments from their IRB
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a
safety issue or makes eligibility criteria more restrictive, sites will not be permitted to
continuing enrolling new participants until the participating site IRB approval has been
granted.
The following documents must be provided to MSKCC for each amendment within the stated timelines:
• Participating Site IRB approval
• Participating Site IRB approved informed consent form and HIPAA authorization
16.3.2 Additional IRB Correspondence
Continuing Review Approval The Continuing Review Approval letter from the participating site’s IRB and the most current approved version of the informed consent form should be submitted to MSKCC within 7 days
Amended: 06-APR-2016 Page 23 of 29
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
of expiration. Failure to submit the re-approval in the stated timeline will result in suspension of study activities.
Deviations and Violations A protocol deviation on this study is defined as a request to treat a research participant who
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in
their study plan. If a deviation from this protocol is proposed for a potential or existing
participant at MSKCC or a participating site, approval from the MSKCC IRB/PB is required
prior to the action. Participating sites should contact the MSKCC PI who will in turn seek
approval from the MSKCC IRB/PB.
A protocol violation is anything that occurs with a participant, which deviated from the
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are
identified after they occur, the participating site should report to MSKCC as soon as possible.
The MSKCC PI will in turn report the violation to the MSKCC IRB/PB.
Participating sites should report deviations and violations to their institution’s IRBs as soon as possible per that site’s institutional guidelines. Approvals/acknowledgments from the participating site IRB for protocol deviations and violations should be submitted to MSKCC as received.
Other correspondence Participating sites should submit other correspondence to their institution’s IRB according to local guidelines, and submit copies of that correspondence to MSKCC.
16.3.3 Document maintenance
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to
enable the implementation of the protocol to be fully documented and the data to be
subsequently verified.
The participating sites will ensure that all participating site IRB correspondence (IRB
approval letters referencing protocol version date and amendment number, IRB approved
protocol, appendices, informed consent forms, deviations, violations, and approval of
continuing reviews) is maintained in the regulatory binder on site and sent to MSKCC.
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper
or electronic.
After study closure, the participating site will maintain all source documents, study related
documents and CRFs for 3 years.
16.4 Noncompliance
If a participating site is noncompliant with the protocol document , accrual privileges may be suspended and/or contract payments may be withheld (if applicable), until the outstanding issues have been resolved.
17.0 PROTECTION OF HUMAN SUBJECTS
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MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
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This study intends to obtain more in-depth information about the safety and feasibility of two
commercially available drugs, enoxaparin and aspirin, in cancer patients with acute ischemic
stroke. The findings of the proposed pilot study will enable the planning and development of
a larger, fully-powered clinical trial that will assess for efficacy.
The potential risks for participants in this study are easy brusing, skin irritation, pain at the
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
Amended: 06-APR-2016 Page 25 of 29
MSKCC)
• Medical record number
• Disease/histology (if applicable)
• Protocol number and title
Data needing to be entered:
• The date the adverse event occurred
• The adverse event
• Relationship of the adverse event to the treatment (drug, device, or intervention)
• If the AE was expected
• The severity of the AE
• The intervention
• Detailed text that includes the following
o An explanation of how the AE was handled
o A description of the subject’s condition
o Indication if the subject remains in the study
o If an amendment will need to be made to the protocol and/or consent form.
The PI’s signature and the date it was signed are required on the completed report.
17.2.1 Serious Adverse Event (SAE) Reporting for Participating Sites
Responsibility of Participating Sites
• Participating sites are responsible for reporting all SAEs to their local IRB per local
guidelines. Local IRB SAE approvals/acknowledgements must be sent to MSK upon
receipt.
• Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail
within 3 calendar days of learning of the event.
• Participating sites should notify the MSKCC PI of any grade 5 event immediately.
• Participating sites should use the SAE Report Form found in MSKCC’s internet-based
Clinical Research Database, CRDBi-Multicenter, to report SAEs to MSKCC.
SAE contact information for the Coordinating Center is listed below:
PI: Lisa M. DeAngelis, MD 1275 York Avenue New York, NY 10065 Tel 212-639-7523 Fax 212-717-3296
Co-PI: Babak Navi, MD
353 E 68th Street New York, NY 10065
MEMORIAL SLOAN-KETTERING CANCER CENTER IRB PROTOCOL
IRB#: 12-264 A(11)
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Tel 212-639-7123
Research Study Assistant I: Benjamin Weill Department of Neurology Memorial Sloan-Kettering Cancer Center
160 E 53rd Street, 2nd Floor New York, NY 10022 Tel: 212.610.0348 Fax: 646.227.2461 Email [email protected]
Responsibility of MSKCC
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC IRB/PB as specified in 17.2.1
• The MSKCC PI is responsible for informing all participating sites about all deaths and unexpected SAEs that are possibly, probably, or definitely related to the study drug within 30 days of receiving the stamped SAE from the MSKCC IRB/PB.
• Any report pertaining to a grade 5 event will be distributed to the participating sites as soon as possible.
17.3 Safety Reports
• MSKCC will distribute outside safety reports to the participating sites immediately upon
receipt.
• MSKCC must submit outside safety reports to the MSKCC IRB/PB according to institutional guidelines.
• Participating sites must submit safety reports to their institution’s IRBs within 30 days of receipt from MSKCC or per participating site guidelines.
18.0 INFORMED CONSENT PROCEDURES
Before protocol-specified procedures are carried out, consenting professionals will explain full
details of the protocol and study procedures as well as the risks involved to participants prior
to their inclusion in the study. Participants will also be informed that they are free to withdraw
from the study at any time. All participants must sign an IRB/PB-approved consent form
indicating their consent to participate. This consent form meets the requirements of the Code
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The
consent form will include the following:
1. The nature and objectives, potential risks and benefits of the intended study.
2. The length of study and the likely follow-up required.
3. Alternatives to the proposed study. (This will include available standard and
investigational therapies. In addition, patients will be offered an option of supportive
care for therapeutic studies.)
4. The name of the investigator(s) responsible for the protocol.
5. The right of the participant to accept or refuse study interventions/interactions and to